PROJECT SUMMARY/ABSTRACT Obesity is a well-known cardiometabolic disease risk factor and growing public health problem. However, little is known about the impact of muscle mass and quality on cardiometabolic risk, including type 2 diabetes (DM), especially in young adults with overweight/obesity. The proposed research has the potential to identify targets for the prevention and treatment of this public health problem. The central hypothesis is that relative sarcopenia (i.e. low muscle mass relative to BMI) and impaired muscle quality (i.e. intramyocellular lipid (IMCL) and mitochondrial dysfunction) contribute to higher DM risk over time in young adults with overweight/obesity. We also hypothesize that common genetic variants associated with insulin resistance, as well as obesity-related relative hormone deficiencies, contribute to relative sarcopenia and impaired muscle quality and lead to higher DM risk. The candidate is an Instructor of Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH) who is highly qualified for and deeply committed to developing a career as an independent investigator. Her short-term goal is to develop the skills and obtain the preliminary data necessary to make the transition to her first R-level independent NIH grant-supported research. Her long- term goal is to become an independent patient-oriented researcher leveraging genetic epidemiology, endocrine physiology and sophisticated imaging techniques to elucidate mechanisms that may contribute to increased cardiometabolic risk in young adults with overweight/obesity, and to identify potential targets for both prevention and treatment. She has an outstanding track record of success, including awards, pilot grants and publications, and is supported by an expert and highly invested mentorship team composed of successful, NIH-supported clinical investigators in Neuroendocrinology, Radiology, Epidemiology and Genetic Epidemiology. She and her mentors have designed a targeted training plan consisting of co-mentorship and a didactic program. The institutional environment is outstanding at MGH and Harvard Medical School, with multiple resources available from the MGH Department of Medicine, the MGH Division of Clinical Research, and the Harvard Clinical and Translational Science Center, all of which offer a myriad of didactic opportunities, facilities and support to the candidate. The Neuroendocrine Unit and Department of Medicine have made a strong commitment to the candidate, including 90% protected time, space, study coordinator support and a faculty appointment, with the goal of fostering the candidate's career as an independent investigator.